Versican Facilitates Chondrocyte Differentiation and Regulates Joint Morphogenesis

Choocheep, Kanyamas; Hatano, Sonoko; Takagi, Hidekazu; Watanabe, Hiroki; Kimata, Koji; Kongtawelert, Prachya; Watanabe, Hideto

doi:10.1074/jbc.m109.096479

Cited by 99 publications

(88 citation statements)

References 44 publications

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“…35 In addition, we previously reported that Vcan regulates local concentrations of TGFb. 19 TGFb was strongly immunostained in the outer region of the QRsP11/Vcan Cre tumor masses and moderately on the inside, whereas there was little immunostaining in the tumor masses from QRsP11/Vcan GFP mice (Fig. 3a, TGFb).…”

Section: Absence Of Versican Upregulates Ha-and Tgfb-mediated Signal mentioning

confidence: 97%

“…X-gal staining was performed as previously described. 19 Images were obtained using an Olympus BX50 microscope and Olympus DP71 digital camera.…”

Section: Molecular Cancer Biologymentioning

confidence: 99%

“…13 The C-terminal G3 domain binds other ECM molecules such as fibrillin-1, 14 fibulin-1 and -2, 15,16 and tenascins, 15,17 and these supramolecular complexes regulate TGFb and BMP signaling. 18,19 CS chains in the center bind cytokines, 15,20 which may regulate their signaling. Vcan is mainly expressed by mesenchymal cells and are also expressed in some cancer cells.…”

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confidence: 99%

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Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Fanhchaksai

Okada

Nagai

et al. 2015

Intl Journal of Cancer

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The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed versican, the role of host stromal versican is not yet understood. In this study, we demonstrate that versican is an important molecule in the functional ECM structure and maintaining cancer-associated fibroblasts, using versican-negative QRsP11 fibrosarcoma cells. By their subcutaneous injection with cre-expressing adenoviruses to versican-floxed mice, we demonstrate that loss of host stromal versican facilitates tumor cell proliferation, and following angiogenesis, decreases cancer-associated fibroblasts, diminishes collagen fibers and alters hyaluronan distribution, concomitant with upregulation of hyaluronan, TGFb and VEGFmediated signaling. When the versican V3 variant consisting of G1 and G3 domains was expressed in tumor cells, it was integrated into the ECM, regained collagen fibers and cancer-associated fibroblasts and resulted in successful recovery of tumor growth inhibition, indicating that whatever cells produce, the G1 and G3 domains are adequate for versican function. Collectively, our results indicate a dynamic function of versican in the ECM that regulates tumor cell behavior. A greater understanding of the regulation of versican expression may contribute to the development of cancer therapies.Cancer cell behavior is largely affected by its microenvironment (such as the stroma), which comprises the extracellular matrix (ECM), fibroblasts and blood vessels.

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Section: Absence Of Versican Upregulates Ha-and Tgfb-mediated Signal mentioning

confidence: 97%

“…X-gal staining was performed as previously described. 19 Images were obtained using an Olympus BX50 microscope and Olympus DP71 digital camera.…”

Section: Molecular Cancer Biologymentioning

confidence: 99%

mentioning

confidence: 99%

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Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Fanhchaksai

Okada

Nagai

et al. 2015

Intl Journal of Cancer

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“…42 Conditional knockout of versican has demonstrated its importance both during chondrogenesis and in binding the profibrotic cytokine TGF-β. 43 Versican is a major component of the early fibroproliferative matrix in lung fibrosis where its deposition is associated with fibroblast migration and proliferation, preceding collagen deposition. [44][45][46] It is also associated with the neointima in atherosclerosis and restenosis.…”

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confidence: 99%

Versican: a novel modulator of hepatic fibrosis

Bukong

Maurice

Chahal

et al. 2016

Laboratory Investigation

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Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrinlike and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE 1401 and G1-DPEAAE 441 ). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.

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“…Thus, the negative charge in various positions along the GAG chains is due to the sugar acid residues and/or sulfate groups (Prydz and Dalen, 2000). GAGs have been known to play many roles in both physiological and pathological conditions or diseases, including signaling activity during chondrocyte differentiation (Choocheep et al, 2010), angiogenesis, anti-coagulation, axonal growth, wound healing, pulmonary and vascular diseases, and tumor progression (Gandhi and Mancera, 2008). Additionally, chondroitin sulfate and hyaluronic acid have been reported to suppress cartilage degradation for the treatment of osteoarthritis (Monfort et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Detection of a Non-animal Source of Glycosaminoglycans from Edible Mushrooms in Northern Thailand

Choocheep¹,

Nathip²

2018

CMUJNS

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Several kinds of cultivated or local edible mushrooms exist in northern Thailand. While their nutritional features have been extensively analyzed, the presence of phytochemicals and glycosaminoglycans has yet to be investigated. Thus, in this study, we examined the presence of phytochemicals and glycosaminoglycans from 10 cultivated or local mushrooms: milk white russula, hygroscopic earthstar, log white fungi, log black fungi, shitake mushroom, rosy russula, sajor-caju mushroom, Jew's ear, bolete, and straw mushroom. Phytochemical analysis revealed the presence of carbohydrates, amino acids, and flavonoids in the extracts from most of the mushrooms. We detected glycosaminoglycans in all of the extracts using dimethylmethylene blue (DMMB) dye-binding assay and UVVis spectrophotometry. Hygroscopic earthstar contained the most glycosaminoglycans and sajor-caju mushroom the least. However, we were unable to distinguish the types of glycosaminoglycans, which should be considered for future study. In summary, the phytochemicals found here are crucial non-animal dietary sources of carbohydrates, amino acids, and antioxidants. In addition, the glycosaminoglycans detected in the mushroom extracts in this study potentially offer a non-animal source of glycosaminoglycans that may have clinical applications, apart from their nutritive value.

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Versican Facilitates Chondrocyte Differentiation and Regulates Joint Morphogenesis

Abstract: . These results suggest that versican facilitates chondrogenesis and joint morphogenesis, by localizing TGF-␤ in the extracellular matrix and regulating its signaling.

Cited by 99 publications

References 44 publications

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Versican: a novel modulator of hepatic fibrosis

Detection of a Non-animal Source of Glycosaminoglycans from Edible Mushrooms in Northern Thailand

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